ABSTRACT Malaria? ?remains? ?endemic? ?in? ?sub-Saharan? ?Africa? ?in? ?large? ?part? ?due? ?to? ?continued? ?evolution? ?and? ?spread? ?of? ?drug resistance? ?which? ?undermines? ?ongoing? ?large-scale? ?control? ?and? ?elimination? ?efforts.? ?We? ?will? ?leverage high-throughput? ?genotyping? ?of? ?parasites? ?using? ?a? ?state-of-the-art? ?panel? ?of? ?molecular? ?inversion? ?probes? ?(MIPs)? ?for targeted? ?sequencing? ?of? ?thousands? ?of? ?resistance? ?and? ?neutral? ?loci? ?across? ?thousands? ?of? ?infections? ?covering? ?the entire? ?Democratic? ?Republic? ?of? ?Congo? ?(DRC)? ?and? ?select? ?areas? ?in? ?bordering? ?countries.? ?This? ?will? ?provide? ?us? ?a? ?map with? ?an? ?unprecedented? ?scale? ?and? ?resolution? ?to? ?define? ?the? ?evolution? ?and? ?spread? ?of? ?antimalarial? ?resistance mutations.? ?In? ?this? ?project,? ?we? ?will? ?first? ?develop? ?our? ?genotyping? ?panel? ?which? ?should? ?provide? ?a? ?high-resolution? ?tool for? ?studying? ?all? ?known? ?drug? ?resistance? ?loci? ?and? ?general? ?parasite? ?population? ?structure? ?in? ?this? ?and? ?other? ?settings. Applying? ?this? ?to? ?well? ?annotated? ?samples? ?from? ?across? ?the? ?DRC? ?and? ?bordering? ?countries,? ?we? ?will? ?define? ?the prevalence? ?of? ?drug? ?resistance? ?mutations? ?and? ?define? ?them? ?based? ?on? ?their? ?genetic? ?haplotypes? ?which? ?act? ?as? ?a unique? ?fingerprints.? ?We? ?will? ?then? ?map? ?these? ?drug? ?resistance? ?haplotypes? ?and? ?study? ?their? ?spread? ?and? ?spatial associations? ?and? ?further? ?examine? ?their? ?epidemiologic? ?associations? ?and? ?interactions.? ?Onto? ?this? ?detailed? ?spatial map,? ?we? ?will? ?? ?examine? ?specific? ?locales? ?of? ?interest? ?for? ?temporal? ?changes.? ?? ?These? ?focal? ?regions? ?in? ?the? ?DRC represent? ?diverse? ?ecologic? ?and? ?demographic? ?features? ?that? ?likely? ?impact? ?resistance? ?spread? ?and? ?evolution including? ?areas? ?with? ?minimal? ?health? ?care? ?infrastructure? ?and? ?ongoing? ?regions? ?of? ?conflict.? ?Our? ?final? ?work? ?will? ?be? ?to apply? ?more? ?sophisticated? ?models? ?to? ?the? ?rich? ?sequence? ?data? ?in? ?order? ?to? ?estimate? ?the? ?flow? ?of? ?parasites? ?and resistance? ?mutations? ?within? ?and? ?between? ?the? ?DRC.? ?This? ?includes? ?the? ?development? ?of? ?new? ?? ?population? ?structure models? ?(MALECOT)? ?incorporating? ?parasite? ?infections? ?that? ?have? ?multiple? ?strains? ?allowing? ?for? ?a? ?better understanding? ?of? ?the? ?full? ?dataset? ?as? ?in? ?polyclonal? ?infections? ?are? ?often? ?the? ?majority? ?in? ?endemic? ?African? ?countries. This? ?model? ?should? ?be? ?broadly? ?applicable? ?to? ?other? ?studies? ?of? ?malaria? ?or? ?infections? ?with? ?mixed? ?strains.? ?We? ?will also? ?leverage? ?? ?spatially? ?explicit? ?models? ?to? ?define? ?general? ?parasite? ?flow? ?in? ?both? ?relative? ?and? ?absolute? ?terms comparing? ?and? ?contrasting? ?to? ?the? ?flow? ?of? ?resistant? ?parasites.? ?This? ?work? ?will? ?provide? ?the? ?patterns? ?of? ?general? ?gene flow? ?and? ?barriers? ?on? ?the? ?spread? ?of? ?specific? ?drug? ?resistance? ?alleles? ?and? ?haplotypes.? ?In? ?summary,? ?not? ?only? ?will this? ?project? ?enhance? ?our? ?understanding? ?of? ?malaria? ?landscape? ?genetics? ?and? ?the? ?evolution? ?and? ?spread? ?of antimalarial? ?resistance,? ?it? ?will? ?provide? ?tools? ?and? ?analysis? ?framework? ?for? ?improving? ?public? ?health? ?interventions that? ?will? ?directly? ?inform? ?the? ?DRC? ?National? ?Malaria? ?Control? ?Program.